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Database: UniProt
Entry: KCNA6_HUMAN
LinkDB: KCNA6_HUMAN
Original site: KCNA6_HUMAN 
ID   KCNA6_HUMAN             Reviewed;         529 AA.
AC   P17658;
DT   01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1990, sequence version 1.
DT   24-JAN-2024, entry version 198.
DE   RecName: Full=Potassium voltage-gated channel subfamily A member 6;
DE   AltName: Full=Voltage-gated potassium channel HBK2 {ECO:0000303|PubMed:2347305};
DE   AltName: Full=Voltage-gated potassium channel subunit Kv1.6;
GN   Name=KCNA6;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBCELLULAR LOCATION.
RC   TISSUE=Brain;
RX   PubMed=2347305; DOI=10.1002/j.1460-2075.1990.tb08299.x;
RA   Grupe A., Schroeter K.H., Ruppersberg J.P., Stocker M., Drewes T.,
RA   Beckh S., Pongs O.;
RT   "Cloning and expression of a human voltage-gated potassium channel. A novel
RT   member of the RCK potassium channel family.";
RL   EMBO J. 9:1749-1756(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=14575698; DOI=10.1016/j.bbrc.2003.09.167;
RA   Guihard G., Bellocq C., Grelet E., Escande D.;
RT   "Human Kv1.6 current displays a C-type-like inactivation when re-expressed
RT   in cos-7 cells.";
RL   Biochem. Biophys. Res. Commun. 311:83-89(2003).
RN   [4]
RP   VARIANTS GLU-261; PHE-447; ILE-449 AND LEU-456, AND CHARACTERIZATION OF
RP   VARIANTS PHE-447; ILE-449 AND LEU-456.
RX   PubMed=36318112; DOI=10.1111/epi.17455;
RG   SYNAPS Study Group;
RA   Salpietro V., Galassi-Deforie V., Efthymiou S., O'Connor E., Marce-Grau A.,
RA   Maroofian R., Striano P., Zara F., Morrow M., Reich A., Blevins A.,
RA   Sala-Coromina J., Accogli A., Fortuna S., Alesandrini M., Au P.Y.B.,
RA   Singhal N.S., Cogne B., Isidor B., Hanna M.G., Macaya A., Kullmann D.M.,
RA   Houlden H., Maennikkoe R.;
RT   "De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in
RT   patients with epilepsy.";
RL   Epilepsia 0:0-0(2022).
CC   -!- FUNCTION: Voltage-gated potassium channel that mediates transmembrane
CC       potassium transport in excitable membranes. Forms tetrameric potassium-
CC       selective channels through which potassium ions pass in accordance with
CC       their electrochemical gradient (PubMed:2347305, PubMed:14575698). The
CC       channel alternates between opened and closed conformations in response
CC       to the voltage difference across the membrane (PubMed:2347305,
CC       PubMed:14575698). Can form functional homotetrameric channels and
CC       heterotetrameric channels that contain variable proportions of KCNA1,
CC       KCNA2, KCNA4, KCNA6, and possibly other family members as well; channel
CC       properties depend on the type of alpha subunits that are part of the
CC       channel (By similarity). Channel properties are modulated by
CC       cytoplasmic beta subunits that regulate the subcellular location of the
CC       alpha subunits and promote rapid inactivation (By similarity).
CC       Homotetrameric channels display rapid activation and slow inactivation
CC       (PubMed:2347305). {ECO:0000250|UniProtKB:P17659,
CC       ECO:0000269|PubMed:14575698, ECO:0000269|PubMed:2347305}.
CC   -!- SUBUNIT: Homotetramer and heterotetramer of potassium channel proteins
CC       (By similarity). Interacts with KCNAB1 and KCNAB2 (By similarity).
CC       {ECO:0000250|UniProtKB:P17659, ECO:0000305}.
CC   -!- INTERACTION:
CC       P17658; Q9UPQ8: DOLK; NbExp=4; IntAct=EBI-6426142, EBI-8645574;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14575698,
CC       ECO:0000269|PubMed:2347305}; Multi-pass membrane protein {ECO:0000305}.
CC   -!- DOMAIN: The N-terminus may be important in determining the rate of
CC       inactivation of the channel while the tail may play a role in
CC       modulation of channel activity and/or targeting of the channel to
CC       specific subcellular compartments.
CC   -!- DOMAIN: The transmembrane segment S4 functions as a voltage-sensor and
CC       is characterized by a series of positively charged amino acids at every
CC       third position. Channel opening and closing is effected by a
CC       conformation change that affects the position and orientation of the
CC       voltage-sensor paddle formed by S3 and S4 within the membrane. A
CC       transmembrane electric field that is positive inside would push the
CC       positively charged S4 segment outwards, thereby opening the pore, while
CC       a field that is negative inside would pull the S4 segment inwards and
CC       close the pore. Changes in the position and orientation of S4 are then
CC       transmitted to the activation gate formed by the inner helix bundle via
CC       the S4-S5 linker region. {ECO:0000250|UniProtKB:P63142}.
CC   -!- SIMILARITY: Belongs to the potassium channel family. A (Shaker) (TC
CC       1.A.1.2) subfamily. Kv1.6/KCNA6 sub-subfamily. {ECO:0000305}.
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DR   EMBL; X17622; CAA35623.1; -; mRNA.
DR   EMBL; BC069355; AAH69355.1; -; mRNA.
DR   CCDS; CCDS8534.1; -.
DR   PIR; S12787; S12787.
DR   RefSeq; NP_002226.1; NM_002235.3.
DR   RefSeq; XP_005253743.1; XM_005253686.3.
DR   RefSeq; XP_011519257.1; XM_011520955.2.
DR   RefSeq; XP_016874759.1; XM_017019270.1.
DR   RefSeq; XP_016874760.1; XM_017019271.1.
DR   RefSeq; XP_016874761.1; XM_017019272.1.
DR   AlphaFoldDB; P17658; -.
DR   SMR; P17658; -.
DR   BioGRID; 109944; 18.
DR   IntAct; P17658; 5.
DR   STRING; 9606.ENSP00000280684; -.
DR   BindingDB; P17658; -.
DR   ChEMBL; CHEMBL5279; -.
DR   DrugBank; DB06637; Dalfampridine.
DR   DrugBank; DB00228; Enflurane.
DR   DrugBank; DB01110; Miconazole.
DR   DrugBank; DB01069; Promethazine.
DR   DrugCentral; P17658; -.
DR   GuidetoPHARMACOLOGY; 543; -.
DR   TCDB; 1.A.1.2.29; the voltage-gated ion channel (vic) superfamily.
DR   iPTMnet; P17658; -.
DR   PhosphoSitePlus; P17658; -.
DR   BioMuta; HGNC:6225; -.
DR   DMDM; 116434; -.
DR   MassIVE; P17658; -.
DR   PaxDb; 9606-ENSP00000280684; -.
DR   PeptideAtlas; P17658; -.
DR   ProteomicsDB; 53501; -.
DR   ABCD; P17658; 1 sequenced antibody.
DR   Antibodypedia; 3161; 138 antibodies from 22 providers.
DR   DNASU; 3742; -.
DR   Ensembl; ENST00000280684.4; ENSP00000280684.3; ENSG00000151079.8.
DR   GeneID; 3742; -.
DR   KEGG; hsa:3742; -.
DR   MANE-Select; ENST00000280684.4; ENSP00000280684.3; NM_002235.5; NP_002226.1.
DR   UCSC; uc001qng.4; human.
DR   AGR; HGNC:6225; -.
DR   CTD; 3742; -.
DR   DisGeNET; 3742; -.
DR   GeneCards; KCNA6; -.
DR   HGNC; HGNC:6225; KCNA6.
DR   HPA; ENSG00000151079; Tissue enriched (brain).
DR   MIM; 176257; gene.
DR   neXtProt; NX_P17658; -.
DR   OpenTargets; ENSG00000151079; -.
DR   PharmGKB; PA30022; -.
DR   VEuPathDB; HostDB:ENSG00000151079; -.
DR   eggNOG; KOG1545; Eukaryota.
DR   GeneTree; ENSGT00940000162469; -.
DR   HOGENOM; CLU_011722_4_0_1; -.
DR   InParanoid; P17658; -.
DR   OMA; STPHRVY; -.
DR   OrthoDB; 1478695at2759; -.
DR   PhylomeDB; P17658; -.
DR   TreeFam; TF313103; -.
DR   PathwayCommons; P17658; -.
DR   Reactome; R-HSA-1296072; Voltage gated Potassium channels.
DR   SignaLink; P17658; -.
DR   BioGRID-ORCS; 3742; 20 hits in 1145 CRISPR screens.
DR   ChiTaRS; KCNA6; human.
DR   GeneWiki; KCNA6; -.
DR   GenomeRNAi; 3742; -.
DR   Pharos; P17658; Tclin.
DR   PRO; PR:P17658; -.
DR   Proteomes; UP000005640; Chromosome 12.
DR   RNAct; P17658; Protein.
DR   Bgee; ENSG00000151079; Expressed in cortical plate and 76 other cell types or tissues.
DR   Genevisible; P17658; HS.
DR   GO; GO:0043679; C:axon terminus; IEA:Ensembl.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0034705; C:potassium channel complex; ISS:UniProtKB.
DR   GO; GO:0008076; C:voltage-gated potassium channel complex; ISS:UniProtKB.
DR   GO; GO:0005251; F:delayed rectifier potassium channel activity; IDA:UniProtKB.
DR   GO; GO:0005249; F:voltage-gated potassium channel activity; TAS:ProtInc.
DR   GO; GO:0071805; P:potassium ion transmembrane transport; IDA:UniProtKB.
DR   GO; GO:0006813; P:potassium ion transport; TAS:ProtInc.
DR   GO; GO:0051260; P:protein homooligomerization; IEA:InterPro.
DR   CDD; cd18407; BTB_POZ_KCNA6; 1.
DR   Gene3D; 1.10.287.70; -; 1.
DR   Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 1.
DR   InterPro; IPR000210; BTB/POZ_dom.
DR   InterPro; IPR005821; Ion_trans_dom.
DR   InterPro; IPR003968; K_chnl_volt-dep_Kv.
DR   InterPro; IPR003972; K_chnl_volt-dep_Kv1.
DR   InterPro; IPR004053; KCNA6.
DR   InterPro; IPR046988; KCNA6_BTB_POZ.
DR   InterPro; IPR011333; SKP1/BTB/POZ_sf.
DR   InterPro; IPR003131; T1-type_BTB.
DR   InterPro; IPR027359; Volt_channel_dom_sf.
DR   PANTHER; PTHR11537:SF104; POTASSIUM VOLTAGE-GATED CHANNEL SUBFAMILY A MEMBER 6; 1.
DR   PANTHER; PTHR11537; VOLTAGE-GATED POTASSIUM CHANNEL; 1.
DR   Pfam; PF02214; BTB_2; 1.
DR   Pfam; PF00520; Ion_trans; 1.
DR   PRINTS; PR00169; KCHANNEL.
DR   PRINTS; PR01513; KV16CHANNEL.
DR   PRINTS; PR01491; KVCHANNEL.
DR   PRINTS; PR01496; SHAKERCHANEL.
DR   SMART; SM00225; BTB; 1.
DR   SUPFAM; SSF54695; POZ domain; 1.
DR   SUPFAM; SSF81324; Voltage-gated potassium channels; 1.
PE   1: Evidence at protein level;
KW   Cell membrane; Ion channel; Ion transport; Lipoprotein; Membrane;
KW   Palmitate; Phosphoprotein; Potassium; Potassium channel;
KW   Potassium transport; Reference proteome; Transmembrane;
KW   Transmembrane helix; Transport; Voltage-gated channel.
FT   CHAIN           1..529
FT                   /note="Potassium voltage-gated channel subfamily A member
FT                   6"
FT                   /id="PRO_0000053990"
FT   TOPO_DOM        1..171
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TRANSMEM        172..193
FT                   /note="Helical; Name=Segment S1"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TOPO_DOM        194..262
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TRANSMEM        263..284
FT                   /note="Helical; Name=Segment S2"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TOPO_DOM        285..295
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TRANSMEM        296..316
FT                   /note="Helical; Name=Segment S3"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TOPO_DOM        317..337
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TRANSMEM        338..358
FT                   /note="Helical; Voltage-sensor; Name=Segment S4"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TOPO_DOM        359..373
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TRANSMEM        374..395
FT                   /note="Helical; Name=Segment S5"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TOPO_DOM        396..409
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   INTRAMEM        410..421
FT                   /note="Helical; Name=Pore helix"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   INTRAMEM        422..429
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TOPO_DOM        430..436
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TRANSMEM        437..465
FT                   /note="Helical; Name=Segment S6"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   TOPO_DOM        466..529
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   REGION          1..33
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          210..233
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          360..373
FT                   /note="S4-S5 linker"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   REGION          488..513
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           422..427
FT                   /note="Selectivity filter"
FT                   /evidence="ECO:0000250|UniProtKB:P63142"
FT   MOTIF           527..529
FT                   /note="PDZ-binding"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         3
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61923"
FT   MOD_RES         511
FT                   /note="Phosphoserine; by PKA"
FT                   /evidence="ECO:0000305"
FT   LIPID           285
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000255"
FT   VARIANT         261
FT                   /note="D -> E (found in a patient with neurodevelopmental
FT                   anomalies; uncertain significance)"
FT                   /evidence="ECO:0000269|PubMed:36318112"
FT                   /id="VAR_087560"
FT   VARIANT         447
FT                   /note="V -> F (found in a patient with epilepsy but without
FT                   evidence of neurodevelopmental impairment; uncertain
FT                   significance; affects channel properties resulting in
FT                   slower channel deactivation)"
FT                   /evidence="ECO:0000269|PubMed:36318112"
FT                   /id="VAR_087561"
FT   VARIANT         449
FT                   /note="T -> I (found in a patient with epilepsy and
FT                   neurodevelopmental anomalies; uncertain significance;
FT                   affects channel properties resulting in slower channel
FT                   deactivation)"
FT                   /evidence="ECO:0000269|PubMed:36318112"
FT                   /id="VAR_087562"
FT   VARIANT         456
FT                   /note="V -> L (found in a patient with epilepsy and
FT                   neurodevelopmental anomalies; uncertain significance;
FT                   affects channel properties resulting in slower channel
FT                   deactivation)"
FT                   /evidence="ECO:0000269|PubMed:36318112"
FT                   /id="VAR_087563"
SQ   SEQUENCE   529 AA;  58729 MW;  CFF0710A1F9CD69F CRC64;
     MRSEKSLTLA APGEVRGPEG EQQDAGDFPE AGGGGGCCSS ERLVINISGL RFETQLRTLS
     LFPDTLLGDP GRRVRFFDPL RNEYFFDRNR PSFDAILYYY QSGGRLRRPV NVPLDIFLEE
     IRFYQLGDEA LAAFREDEGC LPEGGEDEKP LPSQPFQRQV WLLFEYPESS GPARGIAIVS
     VLVILISIVI FCLETLPQFR VDGRGGNNGG VSRVSPVSRG SQEEEEDEDD SYTFHHGITP
     GEMGTGGSSS LSTLGGSFFT DPFFLVETLC IVWFTFELLV RFSACPSKPA FFRNIMNIID
     LVAIFPYFIT LGTELVQQQE QQPASGGGGQ NGQQAMSLAI LRVIRLVRVF RIFKLSRHSK
     GLQILGKTLQ ASMRELGLLI FFLFIGVILF SSAVYFAEAD DDDSLFPSIP DAFWWAVVTM
     TTVGYGDMYP MTVGGKIVGS LCAIAGVLTI ALPVPVIVSN FNYFYHRETE QEEQGQYTHV
     TCGQPAPDLR ATDNGLGKPD FPEANRERRP SYLPTPHRAY AEKRMLTEV
//
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